Substances which modulate the voltage-gated sodium channel are known as local anesthetics, antiarrythmic drugs, or anticonvulsants. Recent research has shown that sodium channel modulators are effective also as therapeutic drugs for central nervous system diseases and disturbances, such as ischemic central nervous disorder, brain trauma, and spinal cord injury, among others (Trends in Pharmacological Science, 16, 309-316, 1995). Ischemic or traumatic nerve injury entails retention of sodium ions in the local neurons or nerve fibers (Stroke, 20, 1377-1382, 1989) and this sodium retention leads to edematization, abnormal release of various neurotransmitters such as dopamine and glutamates (Trends in Neuroscience, 16, 415-419, 1993), and promotion of calcium ion influx by the Na.sup.+ Ca.sup.2+ exchanger (Neuron, 12, 295-300, 1994) to thereby cause cell injuries.
While BW619C89, lifarizine, riluzole, and certain other compounds are known as sodium channel modulators (Trends in Pharmacological Science, 16, 309-316, 1995), cyclic ethers having amino groups on fused ring systems are not known.
As cyclic ethers having amino groups on fused ring systems, the following compounds, among others, are known.
1) The aminocoumaran compounds of the following formula which has inhibitory activity of lipid peroxidation (EP-A-483772 and its counterpart, JP-A-5-140142). ##STR2##
wherein R.sup.1 and R.sup.2 each represents hydrogen, acyl, alkoxycarbonyl, or an aliphatic or aromatic group which may be substituted; R.sup.3, R.sup.4 and R.sup.5 each represents a hydroxy which may be acylated or an amino, alkoxy or aliphatic group which may be substituted, or two of R.sup.3, R.sup.4 and R.sup.5 may form a carbocycle; R.sup.6 and R.sup.7 each represents an aliphatic group which may be substituted and at least one of R.sup.6 and R.sup.7 has methylene in .alpha.-position; R.sup.8 and R.sup.9 each represents hydrogen or an aliphatic or aromatic group which may be substituted.
2) The aminocoumaran compounds of the following formula which has inhibitory activity of lipid peroxidation (JP-A-6-41123). ##STR3##
wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 may be the same or different and each represents lower alkyl; ring A represents a benzene ring substituted by at least one substituent selected from among lower alkyl, lower alkoxy and halogen.
3) A crystalline salt of an enantiomer of 5-amino-2,4,6,7-tetramethyl-2-(4-phenylpiperidinomethyl)-2,3-dihydrobenzo[ b]furan having inhibitory activity of lipid peroxidation (U.S. Pat. No. 5,552,552).
However, there is not report about the relationship of these compounds with sodium channel modulating activity.
Any sodium channel modulatory substance possessed of satisfactory sodium channel modulating activity coupled with favorable intracranial transfer kinetics and metabolic stability is expected to show good efficacy in central nervous system (CNS) diseases and disorders such as central nervous system ischemia, central nervous system trauma (e.g. brain trauma, spinal cord injury, whiplash injury, etc.), epilepsy, neurodegenerative diseases (e.g. amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Huntington's chorea, Parkinson's disease, diabetic neuropathy, etc.), vascular dementia (e.g. multi-infarct dementia, Binswanger's disease, etc.), manic-depressive psychosis, depression, schizophrenia, chronic pain, trigeminal neuralgia, migraine and cerebral edema. However, no fully satisfactory modulator is available today and there has been a standing need for development of a compound possessed of satisfactory sodium channel modulating activity and qualified for use as a medicine.
The inventors of the present invention explored broadly for compounds having sodium channel modulating activity and succeeded in the creation of a novel compound which is structurally characterized in that the carbon atom in 2-position of a fused cyclic ether has been concurrently substituted by a lower alkyl group and a group of the formula: ##STR4##
wherein each of the symbols has the same meaning as defined below, and is of the formula: ##STR5##
wherein
R.sup.1 and R.sup.2 each represents a hydrogen atom, a lower alkyl which may be substituted or an acyl; PA1 R.sup.3, R.sup.4 and R.sup.5 each represents a lower alkyl which may be substituted or a lower alkoxy which may be substituted, or R.sup.4 and R.sup.5 taken together represent a 5- or 6-membered carbocyclic group; PA1 R.sup.6 represents a lower alkyl; PA1 Ar represents an aromatic group which may be substituted; PA1 ring A represents a 5- to 8-membered nitrogen-containing heterocyclic ring which may be substituted; PA1 X represents a lower alkylene which may be substituted; PA1 Y represents a carbon or nitrogen atom; PA1 Za represents a group of the formula: ##STR6## PA1 R.sup.7 represents a hydrogen atom or an aromatic group which may be substituted; R.sup.10 represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl; PA1 Zb represents a bond or a divalent aliphatic hydrocarbon group which may be substituted and may contain oxygen, nitrogen or sulfur; and PA1 m represents an integer of 1 to 3, or a salt thereof [hereinafter referred to briefly as compound (I)]. PA1 i) a hydrogen atom, PA1 ii) a C.sub.1-6 alkyl which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C.sub.3-6 cycloalkyl, C.sub.2-6 alkynyl, C.sub.2-6 alkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl, C.sub.1-6 alkoxy, C.sub.6-10 aryloxy, C.sub.1-6 alkyl-carbonyl, C.sub.6-10 aryl-carbonyl, C.sub.1-6 alkyl-carbonyloxy, carbamoyl, amidino, imino, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, 3- to 6-membered cyclic amino, C.sub.1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C.sub.1-6 alkylsulfamoyl, di-C.sub.1-6 alkylsulfamoyl, C.sub.1-6 alkylthio, C.sub.6-10 arylthio, C.sub.1-6 alkylsulfinyl, C.sub.6-10 arylsulfinyl, C.sub.1-6 alkylsulfonyl and C.sub.6-10 arylsulfonyl, or PA1 iii) an acyl selected from the group consisting of formyl, C.sub.1-6 alkyl-carbonyl, C.sub.6-10 aryl-carbonyl, C.sub.6-10 aryl-C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, C.sub.6-10 aryl-C.sub.1-6 alkoxy-carbonyl, C.sub.1-6 alkylsulfonyl, C.sub.6-10 arylsulfonyl which may be substituted by 1 to 3 C.sub.1-6 alkyl and C.sub.6-10 aryl-C.sub.1-6 alkylsulfonyl; PA1 R.sup.3, R.sup.4 and R.sup.5 each is PA1 or R.sup.4 and R.sup.5 form, taken together with the respective adjacent carbon atoms, a 5- or 6-membered carbocyclic group selected from the group consisting of a 6-membered aromatic hydrocarbon ring and a 5- or 6-membered cycloalkene; PA1 R.sup.6 is a C.sub.1-6 alkyl; PA1 Ar is i) a C.sub.6-14 aryl or ii) a 5- to 10-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen in addition to carbon, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C.sub.1-3 alkylenedioxy, nitro, cyano, C.sub.1-6 alkyl which may be halogenated, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, C.sub.1-6 alkyl-carbonyl, carboxy, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, sulfo, C.sub.1-6 alkylsulfonyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy; PA1 ring A is a 5- to 8-membered nitrogen-containing heterocyclic ring optionally containing 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen in addition to nitrogen and carbon, which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C.sub.1-3 alkylenedioxy, nitro, cyano, C.sub.1-6 alkyl which may be halogenated, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, C.sub.1-6 alkyl-carbonyl, carboxy, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, sulfo, C.sub.1-6 alkylsulfonyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy; PA1 X represents a C.sub.1-6 alkylene which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-14 aryl, nitro, cyano, hydroxy, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, C.sub.1-6 alkyl-carbonyl, C.sub.6-10 aryloxy and oxo; PA1 Y is i) a nitrogen atom or ii) a group of the formula: EQU &gt;C(R.sup.8)-- PA1 wherein PA1 R.sup.7 is a hydrogen atom or i) a C.sub.6-14 aryl or ii) a 5- to 10-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen in addition to carbon, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C.sub.1-3 alkylenedioxy, nitro, cyano, C.sub.1-6 alkyl which may be halogenated, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, C.sub.1-6 alkyl-carbonyl, carboxy, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, sulfo, C.sub.1-6 alkylsulfonyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy; PA1 R.sup.10 is i) a hydrogen atom, ii) a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.6-14 aryl or C.sub.7-16 aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C.sub.3-6 cycloalkyl, C.sub.2-6 alkynyl, C.sub.2-6 alkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl, C.sub.1-6 alkoxy, C.sub.6-10 aryloxy, C.sub.1-6 alkyl-carbonyl, C.sub.6-10 aryl-carbonyl, C.sub.1-6 alkyl-carbonyloxy, C.sub.6-10 aryl-carbonyloxy, carboxy, C.sub.1-6 alkoxy-carbonyl, carbamoyl, amidino, imino, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, 3- to 6-membered cyclic amino, C.sub.1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C.sub.1-6 alkylsulfamoyl, di-C.sub.1-6 alkylsulfamoyl, C.sub.1-6 alkylthio, C.sub.6-10 arylthio, C.sub.1-6 alkylsulfinyl, C.sub.6-10 arylsulfinyl, C.sub.1-6 alkylsulfonyl and C.sub.6-10 arylsulfonyl, or iii) an acyl selected from the group consisting of formyl, C.sub.1-6 alkyl-carbonyl, C.sub.6-10 aryl-carbonyl, C.sub.6-10 aryl-C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, C.sub.6-10 aryl-C.sub.1-6 alkoxy-carbonyl, C.sub.1-6 alkylsulfonyl, C.sub.6-10 arylsulfonyl which may be substituted by 1 to 3 C.sub.1-6 alkyl and C.sub.6-10 aryl-C.sub.1-6 alkylsulfonyl; and PA1 Zb is a divalent aliphatic hydrocarbon group selected from the group consisting of (i) a C.sub.1-8 alkylene, (ii) a C.sub.2-8 alkenylene, (iii) a C.sub.2-8 alkynylene or (iv) a group of the formula: --(CH.sub.2).sub.p --M--(CH.sub.2).sub.q -- wherein p and q each is an integer of 0 to 8 and p+q is an integer of 1 to 8; M is O, NR.sup.9, S, SO or SO.sub.2, wherein R.sup.9 is a hydrogen atom, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-14 aryl, C.sub.7-11 aralkyl or an acyl selected from the group consisting of formyl, C.sub.1-6 alkyl-carbonyl, C.sub.6-10 aryl-carbonyl, C.sub.6-10 aryl-C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, C.sub.6-10 aryl-C.sub.1-6 alkoxy-carbonyl, C.sub.1-6 alkylsulfonyl, C.sub.6-10 arylsulfonyl which may be substituted by 1 to 3 C.sub.1-6 alkyl and C.sub.6-10 aryl-C.sub.1-6 alkylsulfonyl, each of which divalent group may be substituted by 1 to 5 substituents selected from the group consisting of halogen, nitro, cyano, C.sub.1-6 alkyl which may be halogenated, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, C.sub.6-14 aryl, C.sub.7-11 aralkyl, C.sub.6-10 aryloxy, oxo, formyl, C.sub.1-6 alkyl-carbonyl, C.sub.6-10 aryl-carbonyl, C.sub.6-10 aryl-C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, C.sub.6-10 aryl-C.sub.1-6 alkoxy-carbonyl, C.sub.1-6 alkylsulfonyl, C.sub.6-10 arylsulfonyl which may be substituted by 1 to 3 C.sub.1-6 alkyl and C.sub.6-10 aryl-C.sub.1-6 alkylsulfonyl, PA1 R.sup.3, R.sup.4, R.sup.5, and R.sup.6 each is a C.sub.1-6 alkyl; PA1 Ar is a phenyl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; PA1 ring A is a 6-membered nitrogen-containing heterocyclic ring; PA1 X is methylene; PA1 Y is CH or N; PA1 Za is a group of the formula: ##STR10## PA1 wherein R.sup.7' is a phenyl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; and R.sup.10' is a hydrogen atom; PA1 Zb is a bond or a C.sub.1-6 alkylene which may be substituted by a C.sub.6-10 aryl; and PA1 m is 1 or 2, PA1 R.sup.3, R.sup.4, R.sup.5, and R.sup.6 each is a C.sub.1-6 alkyl; PA1 Ar is a C.sub.6-10 aryl which may substituted by a methylenedioxy; PA1 ring A is a 6-membered nitrogen-containing heterocyclic ring; PA1 X is methylene; PA1 Y is CH or N; PA1 Za is a group of the formula: ##STR11## PA1 wherein R.sup.7a is a hydrogen atom or C.sub.6-10 aryl; PA1 Zb is a bond or a (i) C.sub.1-6 alkylene or (ii) C.sub.2-6 alkenylene group which may be substituted by a C.sub.6-10 aryl; and PA1 m is 1, PA1 R.sup.3, R.sup.4, R.sup.5, and R.sup.6 each is a C.sub.1-6 alkyl; PA1 Ar is a C.sub.6-10 aryl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, methylenedioxy, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; PA1 ring A is a 6-membered nitrogen-containing heterocyclic ring; PA1 X is methylene; PA1 Y is CH or N; PA1 Za is a group of the formula: ##STR12## PA1 wherein R.sup.7b is a hydrogen atom or a C.sub.6-10 aryl which may be substituted by a halogen; and R.sup.10a is a hydrogen atom PA1 or a C.sub.7-11 aralkyl; PA1 Zb is a bond or a divalent group selected from the group consisting of (i) a C.sub.1-6 alkylene, (ii) a C.sub.2-6 alkenylene and (iii) a group of the formula: --(CH.sub.2).sub.p' --M'--(CH.sub.2).sub.q' -- wherein p' and q' each is an integer of 0 to 5, p'+q' is an integer of 1 to 6 and M' is O or NH, each of which divalent group may be substituted by PA1 a C.sub.6-10 aryl; and PA1 m is 1 or 2, PA1 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(diphe nylmethyl)-4-piperidinamine, PA1 (-)-1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(d iphenylmethyl)-4-piperidinamine, PA1 (-)-1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(d iphenylmethyl)-4-piperidinamine, PA1 (1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl)methyl] -N-(diphenylmethyl-4-piperidinamine, PA1 (-)-1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl)meth yl]-N-(diphenylmethyl)-4-piperidinamine, PA1 (+)-1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl)meth yl]-N-(diphenylmethyl)-4-piperidinamine, or a salt thereof, PA1 (i) reacting a compound of the formula: ##STR13## PA1 wherein L represents a leaving group; the other symbols have the same meanings as defined above, or a salt thereof with a compound of the formula: ##STR14## PA1 wherein the respective symbols have the same meanings as defined above, or a salt thereof; PA1 (ii) subjecting a compound of the formula: ##STR15## PA1 wherein the respective symbols have the same meanings as defined above, or a salt thereof to (a) alkylation, (b) acylation or (c) acylation followed by reduction; PA1 (iii) reacting a compound of the formula: ##STR16## PA1 wherein n represents an integer of 1 to 4; the other symbols have the same meanings as defined above, or a salt thereof with a compound of the formula: ##STR17## PA1 wherein R.sup.11 represents a hydrogen atom or a hydrocarbon group which may be substituted; Zd represents a divalent aliphatic hydrocarbon group which may be substituted and may contain oxygen, nitrogen or sulfur; Ar as the same meaning as defined above, or a salt thereof, PA1 (iv) reacting a compound of the formula: ##STR18## PA1 wherein the respective symbols have the same meanings as defined above, or a salt thereof with a compound of the formula: ##STR19## PA1 wherein the respective symbols have the same meanings as defined above, or a salt thereof, optionally followed by reduction; or PA1 (v) subjecting a compound of the formula: ##STR20## PA1 wherein the respective symbols have the same meanings as defined above, or a salt thereof to (a) nitration followed by reduction or (b) diazo coupling reaction followed by reduction, PA1 (S)-2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)methyl]-5-be nzofuranamine, PA1 2,3-dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)methyl]- 5-benzofuranamine, PA1 (-)-2,3-dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)meth yl]-5-benzofuranamine, PA1 (+)-2,3-dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)meth yl]-5-benzofuranamine, PA1 7-tert-butyl-2,3-dihydro-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)methyl] -5-benzofuranamine, PA1 (-)-7-tert-butyl-2,3-dihydro-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)met hyl]-5-benzofuranamine, PA1 (+)-7-tert-butyl-2,3-dihydro-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)met hyl]-5-benzofuranamine, or a salt thereof. PA1 (i) C.sub.1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), PA1 (ii) C.sub.2-6 alkenyl (e.g. vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.), PA1 (iii) C.sub.2-6 alkynyl (e.g. ethynyl, propargyl, butynyl, 1-hexynyl, etc.), PA1 (iv) C.sub.3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), PA1 (v) C.sub.6-14 aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, biphenyl, 2-anthryl, etc.; preferably phenyl), PA1 (vi) C.sub.7-16 aralkyl (e.g. benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.; preferably benzyl). PA1 (i) C.sub.1-8 alkylene (e.g. --CH.sub.2 --, --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --(CH.sub.2).sub.6 --, --(CH.sub.2).sub.7 --, --(CH.sub.2).sub.8 --, etc.), PA1 (ii) C.sub.2-8 alkenylene (e.g. --CH.dbd.CH--, --CH.sub.2 --CH.dbd.CH--, --CH.sub.2 --CH.dbd.CH--CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.dbd.CH--, etc.), PA1 (iii) C.sub.2-8 alkynylene (e.g. --C.tbd.C--, --CH.sub.2 --C.tbd.C--, --CH.sub.2 --C.tbd.C--CH.sub.2 --CH.sub.2 --, etc.), PA1 (iv) group of the formula: --(CH.sub.2).sub.p --M-(CH.sub.2).sub.q -- wherein M represents O, NR.sup.9, S, SO or SO.sub.2 ; p and q each represents an integer of 0 to 8 and p+q represents an integer of 1 to 8. In the above formula R.sup.9 represents a hydrogen atom, C.sub.1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc.), C.sub.3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, etc.), C.sub.6-14 aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, etc.), C.sub.7-11 aralkyl (e.g. benzyl, phenethyl, etc.) or acyl, The "acyl" mentioned just above includes the same groups as mentioned for the "acyl" represented by R.sup.1 or R.sup.2. PA1 wherein R.sup.1 and R.sup.2 each is a hydrogen atom; PA1 R.sup.3, R.sup.4, R.sup.5, and R.sup.6 each is C.sub.1-6 alkyl; PA1 Ar is a phenyl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; PA1 ring A is a 6-membered nitrogen-containing heterocyclic ring; PA1 x is methylene; PA1 Y is CH or N; PA1 Za is a group of the formula: ##STR24## PA1 wherein R.sup.7' is a phenyl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; and R.sup.10' is a hydrogen atom; PA1 Zb is a bond or a C.sub.1-6 alkylene which may be substituted by a C.sub.6-10 aryl; and PA1 m is 1 or 2. PA1 R.sup.1 and R.sup.2 each is a hydrogen atom; PA1 R.sup.3, R.sup.4, R.sup.5 and R.sup.6 each is a C.sub.1-6 alkyl; PA1 Ar is a (i) C.sub.6-10 aryl, (ii) 2-pyridyl, (iii) 3-pyridyl, (iv) 4-pyridyl, (v) 2-indolyl or (vi) 3-indolyl, each of which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C.sub.1-3 alkylenedioxy, nitro, cyano, C.sub.1-6 alkyl which may be halogenated, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, C.sub.1-6 alkyl-carbonyl, carboxy, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, sulfo, C.sub.1-6 alkylsulfonyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy; PA1 ring A is a 6-membered nitrogen-containing heterocyclic ring; PA1 X is methylene; PA1 Y is CH or N; PA1 Za is a group of the formula: ##STR25## PA1 R.sup.7b is a hydrogen atom or a C.sub.6-10 aryl which may be substituted by a halogen; PA1 R.sup.10a is a hydrogen atom or a C.sub.7-11 aralkyl; PA1 Z.sup.b is a bond or a (i) C.sub.1-6 alkylene, (ii) C.sub.2-6 alkenylene or (iii) group of the formula: --(CH.sub.2).sub.p' --M'--(CH.sub.2).sub.q' -- wherein p' and q' each represents an integer of 0 to 5 and p'+q' represents an integer of 1 to 6; M' represents O or NH, each of which may be substituted by a C.sub.6-10 aryl; and PA1 m is 1 or 2. PA1 R.sup.1 and R.sup.2 each is a hydrogen atom; PA1 R.sup.3, R.sup.4, R.sup.5 and R.sup.6 each is a C.sub.1-6 alkyl; PA1 Ar is a C.sub.6-10 aryl which may be substituted by a methylenedioxy; PA1 ring A is a 6-membered nitrogen-containing heterocyclic ring; PA1 X is methylene; PA1 Y is CH or N; PA1 Za is a group of the formula; ##STR26## PA1 R.sup.7a is a hydrogen atom or a C.sub.6-10 aryl; PA1 Zb is (i) a bond or (ii) a C.sub.1-6 alkylene or C.sub.2-6 alkenylene group which may be substituted by a C.sub.6-10 aryl; and PA1 m is 1. PA1 R.sup.1 and R.sup.2 each is a hydrogen atom; PA1 R.sup.3, R.sup.4, R.sup.5 and R.sup.6 each is a C.sub.1-6 alkyl; PA1 Ar is a C.sub.6-10 aryl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, methylenedioxy, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; PA1 ring A is a 6-membered nitrogen-containing heterocyclic ring; PA1 X is methylene; PA1 Y is CH or N; PA1 Za is a group of the formula; ##STR27## PA1 R.sup.7b is a hydrogen atom or a C.sub.6-10 aryl which may be substituted by a halogen; PA1 R.sup.10a is a hydrogen atom or a C.sub.7-11 aralkyl; PA1 Zb is a bond or a (i) C.sub.1-6 alkylene, (ii) C.sub.2-6 alkenylene or (iii) group of the formula: --(CH.sub.2).sub.p' -M'-(CH.sub.2).sub.q' -- wherein p' and q' each represents an integer of 0 to 5 and p'+q' represents an integer of 1 to 6; M' represents O or NH, each of which may be substituted by a C.sub.6-10 aryl; and PA1 m is 1 or 2. PA1 2-[(4-benzyl-1-piperidinyl)methyl]-2,3-dihydro-2,4,6,7-tetramethyl-5-benzof uranamine, PA1 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(diphe nylmethyl)-4-piperidinamine, PA1 (-)-1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(d iphenylmethyl)-4-piperidinamine, PA1 (+)-1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(d iphenylmethyl)-4-piperidinamine, PA1 1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl)methyl]- N-(diphenylmethyl)-4-piperidinamine, PA1 (-)-1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl)meth yl]-N-(diphenylmethyl)-4-piperidinamine, PA1 (+)-1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl)meth yl]-N-(diphenylmethyl)-4-piperidinamine, PA1 2-[[4-diphenylmethoxy)-1-piperidinyl]methyl]-2,3-dihydro-2,4,6,7-tetramethy l-5-benzofuranamine, PA1 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(3,3-d iphenylpropyl)-4-piperidineethylamine, 2,3-dihydro-2,4,6,7-tetramethyl-2-[[4-(2-phenylethyl)-1-piperazinyl]methyl ]-5-benzofuranamine, and salts thereof. PA1 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(diphe nylmethyl)-4-piperidinamine, PA1 (-)-1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(d iphenylmethyl)-4-piperidinamine, PA1 (+)-1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(d iphenylmethyl)-4-piperidinamine, PA1 1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl)methyl]- N-(diphenylmethyl)-4-piperidinamine, PA1 (-)-1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl)meth yl]-N-(diphenylmethyl)-4-piperidinamine, PA1 (+)-1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl)meth yl]-N-(diphenylmethyl)-4-piperidinamine, or a salt thereof. PA1 R.sup.1 and R.sup.2 each is a hydrogen atom, a C.sub.1-6 alkyl or C.sub.1-6 alkyl-carbonyl; PA1 R.sup.3, R.sup.4, R.sup.5 and R.sup.6 each is a C.sub.1-6 alkyl; PA1 ring Aa is a 6- or 7-membered nitrogen-containing heterocyclic ring which may be fused to a benzene ring; PA1 X is methylene; PA1 Y is (i) a group of the formula EQU &gt;C(R.sup.8a)-- PA1 (wherein R.sup.8a represents a hydrogen atom or hydroxy) or (ii) N; PA1 Q is (i) a hydrogen atom , (ii) a C.sub.6-10 aryl or 6-membered nitrogen-containing aromatic group which may be substituted by halogen or C.sub.1-6 alkoxy, or (iii) a group of the formula EQU --Zc'--Ar' PA1 (wherein Zc' represents a C.sub.1-6 alkylene or C.sub.2-6 alkenylene group which may be substituted by C.sub.6-10 aryl or oxo and may contain oxygen; and Ar' represents a C.sub.6-10 aryl); and PA1 m is 1. PA1 (S)-2,3-dihydro-2,4,6,7- tetramethyl-2-[(4-phenyl-1-piperidinyl)methyl]-5-benzofuranamine, PA1 2,3-dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)methyl]- 5-benzofuranamine, PA1 (-)-2,3-dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)meth yl]-5-benzofuranamine, PA1 (+)-2,3-dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)meth yl]-5-benzofuranamine, PA1 7-tert-butyl-2,3-dihydro-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)methyl] -5-benzofuranamine, PA1 (-)-7-tert-butyl-2,3-dihydro-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)met hyl]-5-benzofuranamine, PA1 (+)-7-tert-butyl-2,3-dihydro-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)met hyl]-5-benzofuranamine, or a salt thereof.
wherein
They discovered surprisingly that a compound of the following formula or a salt thereof [hereinafter referred to briefly as compound (Ia)] including compound (I) has very favorable properties required of a sodium channel modulator, for example a good affinity for the sodium channel as well as high stability, and as such is fully satisfactory for use as a medicine. The present invention has been developed on the basis of the above findings: ##STR7##
wherein Q represents a hydrogen atom, an aromatic group which may be substituted or a group of the formula: EQU --Zc--Ar
wherein Zc represents a divalent aliphatic hydrocarbon group which may be substituted and may contain oxygen, nitrogen or sulfur; Ar has the same meaning as defined above; ring Aa represents a 5- to 8-membered nitrogen-containing heterocyclic ring which may be substituted or the corresponding fused benzologue system thereof; the other respective symbols have the same meanings as defined above.